We have shown previously that human exudative neutrophils contain almost 200-fold more cell-associated IL-8 than neutrophils isolated from peripheral blood. In addition we have shown that the addition of thapsigargin, an inhibitor of endoplasmic reticulum Ca2+-ATPase, to isolated peripheral blood neutrophils causes a sustained elevation in [Ca2+]i (attributed to an extracellular influx of Ca2+) and increased expression of mRNA for IL-8. This induction causes a dramatic and relatively specific increase in the production and secretion of IL-8, reaching levels observed in exudative neutrophils isolated from an inflammatory focus in vivo. This past year we have shown that the addition of the chemotactically active doses of the formyl peptide fMLP or leukotriene B4 in the presence of physiologic concentrations of fibrinogen induces peripheral blood neutrophils to synthesize levels of IL-8 found in exudates cells. The induction of IL-8 synthesis by fibrinogen/fMLP or LTB4 is accompanied by an increase in the level of IL-8 mRNA, as shown by RNAse protection assay. Furthermore, the production of cytokines/chemokines is somewhat restricted to IL-8; whereas levels of IL-8 are increased 200 fold, the levels of IL-1beta and TNF-alpha increase ~5-fold. No significant increases in the levels of MIP-1alpha, MIP-1beta, or IL-1ra are observed under these conditions, despite elevated of expression of mRNA for these mediators. Fibrinogen does not alter other functional responses elicited by fMLP in neutrophils; there were no significant changes in the fMLP dose- response curves for superoxide production, degranulation, chemotaxis, or changes in intracellular calcium. The data demonstrate a sensitive neutrophil autocrine mechanism to amplify inflammation through a fibrinogen dependent induction of the synthesis and release of interleukin 8. - Inflammation, neutrophil, interleukin-8, fibrinogen, f-met-leu-phe, leukotriene B4, calcium, thapsigargin